DD139856A5 - Process for the preparation of new thieno (2,3-c) and (3,2-c) pyridine derivatives - Google Patents

Description

Process for the preparation of new Thieno / "2,3-cJ - and - £ 3" 2 - cJ pyridine derivatives !!

Field of application of the invention

The present invention relates to a novel process for the preparation of novel thienopyridine derivatives which are useful in human and veterinary medicine.

Furthermore, the new derivatives can be used as starting materials in the synthesis of compounds which are also useful in the chemical and pharmaceutical industries.

Characteristic of the known technical solutions

Thieno Γ3,2-ο- pyridine derivatives, which are unsubstituted in position 4, are already known from US Pat. No. 3,845,065 , their therapeutic use, in particular as antiinflammatory agents, and processes for their preparation.

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Object of the invention

The object of the invention is to provide a simple and economical process for the preparation of new Thieno £ 2,3-cJ and -p3,2-cJ pyridine derivatives having improved anti-inflammatory activity.

Explanation of the essence of the invention

The object of the invention is to find suitable reaction constituents and suitable reaction conditions for the preparation of novel thieno-2,3-cJ and -p3-2-pyrrole derivatives. ,

The present invention thus provides a process for the preparation of Thieno £ 2,3-cJ and thieno / 73,2-cJ-pyridine derivatives of the general formulas

and

(D (ID

wherein R ₇ . and R _{2 are the} same or different and each represents hydrogen or alkyl, and their pharmaceutically acceptable acid addition salts, which consists in:

a) a compound of the general formula

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OH

04/26/1979

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(VII)

(VIII)

wherein R _x , and Rp have the above meaning, with a SuI-fonylcblorid the general formula

ClSO ₂ R ₃ ,

where R ~ low. Alkyl or phenyl optionally substituted with halogen or lower. Alkyl, condensed in a biphasic solvent system and in the presence of sodium carbonate;

b) the alcohols of the general formulas thus obtained

N-SO ₀ R ₀

(V)

oxidized in a solvent and

(VI)

c) the ketones of the general formulas thus obtained

or

κ.

(HD

(IV)

209 81 4

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with a base of the formula RO ^- M ⁺ , wherein R is optionally branched aliphatic alkyl and M ^{+ is} a cation of an alkali metal, treated in an alcohol of the formula ROH as solvent and at the reflux temperature of the reaction mixture.

The general formulas (I) and (II) can be written in the form of the zwitterions as follows:

ο ^v

R ₂

and

The groups R. and R ₂ are in particular lower alkyl having 1 to 6 carbon atoms, for example methyl.

The essential step of the process according to the invention consists in the treatment of the derivative of the formula (III) or (IV) in which R 1 and R _{2 have} the abovementioned meaning and R 1 denotes lower alkyl, preferably methyl, or optionally halogen or lower alkyl (such as methyl) substituted phenyl, with a base. In the reaction, a sulfinic acid in the form of the salt R-SO ₂ M ⁺ is removed by the action of an alcoholate R0 "" M ⁺ according to the following scheme:

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"M ⁺

(D

In the same way, by treatment of the compound of the formula (IV), the compound of the formula (II) is obtained.

This reaction is carried out by refluxing in an optionally branched aliphatic Cj-C, -oikohol ROH in the presence of the sodium or potassium alkoxide (RO ^- Na ⁺ or RO ^- K ⁺ ). The use of potassium tert. Butylate in tert-butanol is particularly advantageous.

Compounds (III) and (IV) are obtained by oxidation of the corresponding alcohols of formulas (V) and (VI). This reaction is carried out in acetone using a solution of chromic anhydride in sulfuric acid as the oxidizing agent.

The alcohols (V) and (VI) are obtained by condensation of the corresponding 4-, 5 »6,7-Tetrabydrothienopyridine (VII) and (VIII) with a sulfonyl chloride ClSO ₂ R ₃ . This reaction is carried out in the solvent system water-chloroform in the presence of sodium or potassium carbonate *

The derivatives (V) and (VI) wherein R 1 = R ₂ = H and R ₃ = p-tolyl have already been described by JP Maffrand and F. Eloy, J. He. Chem. 1976, I3, 134-7.

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The starting compounds (VII) and (VIII), in which R 'is hydrogen, are likewise described in the abovementioned reference or in IR Patents 2 278 337 and 2 313 055,

In the following, the preparation of a starting compound (VII) used according to the invention, wherein E _x . = CH ", namely 4-hydroxy-2-methyl-4,5,6,7-tetrahydrotbieno £ 2,3-cJ pyridine (R ₂ = H) described in more detail.

A mixture of 30 g (0.237 mol) of 5-methylthiophene-2-carboxaldehyde and 27.4 g (0.261 mol) of aminoacetaldehyde dimetyl acetal in 250 ml of benzene is refluxed for 2 hours in a flask equipped with a Dean-Stark separator and condenser heated. It is then evaporated to dryness and the residue dissolved in 250 ml of ethanol. Thereafter, 13.5 g (0.355 mol) of sodium borohydride are added in portions and the whole allowed to stand overnight at ambient temperature. The excess sodium borohydride is decomposed by adding acetone and the mixture is evaporated to dryness. The residue is taken up in water and extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated to dryness. The resulting oily residue is distilled under reduced pressure, bp 127 ° C / 266 Pa, yield 90%. The thus obtained N- (5 ~ Metbyl-2-thienyl) -methylaminoacetaldebyd-dimetbylacetal is heated hours in 250 ml 6N hydrochloric acid at 60 ⁰ C. 1

It is then evaporated to dryness and the residue is triturated with acetone. The whitish chlorohydrate crystals obtained are recrystallized from acetonitrile, B ¹ P. 120 ⁰ C, Ge total yield 61%.

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Ausführungsbe ispiel

The following examples are intended to illustrate the present invention without, however, being limited thereto.

example 1

Preparation of 7-hydroxythieno [3,2-03 -pyridine (II, R 1 R ₂ = H; derivative 1)

a) Preparation of 7-hydroxy-5-tosyl-4,5,6,7-tetrahydrothieno-3,2-c] -pyridine (VI, R 1 = R ₂ = H, R 1 = p-tolyl)

To a mixture of 45 g (0.234 mol) of 7-hydroxy-4,5,6,7-tetrahydrothieno Γ3,2-οΙ-pyridine chlorobydrate, 100 ml of chloroform and 150 ml of a saturated aqueous potassium carbonate solution is added dropwise at ambient temperature with vigorous mechanical stirring a solution of 45 g (0.234 mol) of p-toluenesulfonyl chloride in 250 ml of chloroform is added and stirring is continued for 4 b. After decanting, the cbloroform phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column (eluent toluene-ethyl acetate 7O) and recrystallized from isopropanol. This white crystals are obtained in a yield of 74%, mp. 120 ⁰ C.

b) Preparation of 7-0xo-5-tosyl-4,5,6,7-tetrabydrothieno-3,2-c; upyridine (IV, R ₁ = R ₂ = H, R ₃ = p -olyl)

28.4 ml of Jones reagent (a solution of 2.50 M chromic anhydride in 8.35 Ν sulfuric acid) is added dropwise

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with stirring and at ambient temperature to a solution of 20.3 g (0.054 mol) of 7-hydroxy-5-tosyl-4,5,6,7-tetrahydrothieno £ 3> 2-c3-pyridine, prepared as described under a), in 250 ml of acetone. Stirring is continued at ambient temperature for 2 hours whereupon the precipitated mineral salts are filtered, the filtrate is evaporated to dryness and the residue is taken up in methylene chloride. The organic phase is washed with an aqueous 5% sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated to dryness. The solid residue is recrystallized from benzene. There are cream-colored crystals in a yield of 79 % , mp. 174 ⁰ C.

c) Preparation of 7-hydroxy-thieno-3,2-c "3-pyridine (II, R 1 = R ₂ = H; derivative 1)

Solution of 19.6 g (0.064 mol) of 7-0xo-5-tosyl-4,5,6,7-tetrahydrothieno [ 3,2-cJ-pyridine, prepared as described under b), and 28.6 g (0.255 g) mol) of potassium tert-butoxide in tert-butanol 3OO ^m l is heated in a nitrogen atmosphere for 2 hours at reflux. Evaporation of the solvent in vacuo gives a residue which is taken up in 2N hydrochloric acid. The aqueous phase is extracted with ether, basified by adding conc. Ammonia and evaporated to dryness. The residue is extracted four times with boiling ethyl acetate. The organic extracts are filtered over a kieselgurbett and evaporated to dryness. The solid residue is recrystallized from a mixture of ethanol and acetonitrile. The title compound is obtained in the form of grayish crystals in 72 % yield, mp 180 ^° C.

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Example 2

Preparation of 4-hydroxytbieno-2,3-c7-pyridine (I, H, derivative 2)

a) Preparation of 4-hydroxy-6-tosyl-4,5,6,7-tetrahydrotbieno-2,3-pyridine (V, R 1 = R ₂ = H; R ₃ = p-tolyl)

This compound is prepared in the manner described in Example 1a), starting with 4-hydroxy-4,5,6,7-tetrabydrothieno-2,3-c3-pyridine-chlorohydrate. The title compound is obtained in the form of beige crystals in 86 % yield, bp 13O ⁰ C (isopropanol).

b) Preparation of 4-oxo-6-tosyl-4,5,6,7-tetrahydrothieno-2,3-cipyridine (III, R ₁ = R ₂ = H, R ₃ = p-tolyl)

This compound is prepared in the manner described in Example 1b), starting from the tosylate described under a). The. Compound is obtained in F _orm translucent white crystals in a yield of 98%, mp. 172 ⁰ C (benzene).

c) Preparation of 4-hydroxythieno / "2,3-cJ pyridine (I, R ^ = R ₂ - = H; derivative 2)

^T hese compound is prepared as described in Example Ic) manner, starting from the process described under b) tosylate. It is obtained in a yield of 78% in the form of white crystals, mp 206 ⁰ C (ethanol-cyclohexane).

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Example 3

Preparation of 4-hydroxy-7-niethylthienoj [2,3-cj pyridine (I ₁ R ₁ = H, R ₂ = CH ₃ ; derivative 3).

a) Preparation of 4-hydroxy-7 ^ -methyl-6-tosyl-4,5,7,7-tetrahydrotbieno £ 2,3-0] pyridine (V, R ₁ = H, R ₂ = CH-., R = p-tolyl)

This compound is prepared in the manner described in Example 1a), starting from 4-hydroxy-7-niethyl-4,5j6,7-tetrahydrotbieno £ 2,3-0 3 pyridine-chlorohydrate. It is obtained in a yield of 96 % in the form of whitish crystals, mp. 120 ⁰ C (benzene-cyclobexane).

b) Preparation of 7-methyl-4-oxo-6-tosyl-4,5,6,7-tetrahydrothieno-2,3-cJ-pyridine (III, R ₁ = H, R ₂ = CH ₃ , R ₃ = p tolyl)

This compound is prepared in the manner described in Example 1b), starting from the tosylate described under a). It is obtained in a yield of 90% in the form of white crystals, mp. 164 ⁰ C (benzene-acetone).

c) Preparation of 4-hydroxy-7-methylthieno £ 2,3-0J pyridine (I, R ₁ = H, R ₂ = CH _3; derivative 3)

This compound is prepared in the manner described in Example 1c), starting from the tosylate described under b). Si © is obtained in a yield of 50% in the form of white crystals, mp 220 ° '(cyclohexane-ethanol).

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Example 4

Preparation of 4-hydroxy-2-methyltbieno £ 2,3-cJ pyridine (I, R ₁ .s CH ₃ , R ₂ = H; derivative 4)

a) Preparation of 4-hydroxy-2-methyl-6-tosyl-4,5> 6,7-tetrabydrothieno £ 2,3-cJ pyridine (V, R = CH ₃ , R ₂ = H, R »= p Tolyl).

This compound is prepared in the manner described in Example 1a), starting from 4-hydroxy-2-methyl-4,5,6,7-tetrabydrotbieno Γ2,3-οΐ7 pyridine cblorhydrat is assumed (preparatory preparation). It is obtained in 48 % yield in the form of white crystals, mp 132 ° ((benzene).

b) Preparation of 2-methyl-4-oxo-6-tosyl-4,5,6,7-tetrahydrothieno £ 2.3 ~ cJ pyridine (III, R ₁ = CH ₃ , R ₂ = H, R- = p tolyl)

This compound is prepared in the manner described in Example 1b), starting from the tosylate described under a). It is obtained in a yield of 83 % in the form of whitish crystals, mp 124 ⁰ C.

c) Preparation of 4-hydroxy-2-methylthieno £ 2,3-O-pyridine (I, R ₁ = CH ₃ , R ₂ = H; derivative 4)

This compound is prepared in the manner described in Example 1c), starting from the tosylate described under b). It is obtained in a yield of 36% in the form of grayish crystals, mp 220 ⁰ C (ethanol-acetonitrile). ,

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Example 5

Preparation of 4-hydroxythieno £ 2,3-cJ-pyridine (derivative 2)

In this example, a variant of the method of Example 2 for the preparation of the derivative 2 will be described.

a) Preparation of 4-hydroxy-6-mesyl-4,5,7,7-tetrahydrothieno £ 2,3-cJ pyridine (V, R ₁ = R ₂ = H, R ₃ = CH ₃ )

To a mixture of 50 g (0.26 mol) of 4-hydroxy-4,5,6,7-tetrahydrothieno / 2,3-c7-pyridine hydohydrate, 200 ml of chloroform and 100 ml of a saturated aqueous potassium carbonate solution is added dropwise at ambient temperature and under a high pressure a solution of 30 g (0.26 mol) of methanesulfonyl chloride in 50 ml of chloroform. Rushing is continued for 2 hours at ambient temperature. After decantation, the chloroform phase is washed with dilute hydrochloric acid and then with water and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gives crystals which are recrystallized from methanol. The title compound is obtained orm shiny brown crystals in a yield of 76% in. ^, Pp. 140 ⁰ C (methanol).

b) Preparation of 6-mesyl-4-oxo-4,5,6,7-tetrahydrothieno / "2,3-c7-pyridine (III, R ₁ = R ₂ = H, R ₃ = CH ₃ )

This compound is prepared in the manner described in Example 1b), starting from the methanesulfonate described under a), it is obtained in a yield of 70 % in the form of beige crystals, mp 120 ⁰ C (isopropanol-ethyl acetate).

• 26.4.1979

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c) Preparation of 4-hydroxytbieno-f2,3-c3-pyridine (I, = H)

This compound is prepared in the manner described in Example 1c), starting from the methanesulfonate described under b). It is obtained in a yield of 80 % in the form of white crystals, mp. 206 ⁰ C (etanol-cyclobexane),

The results of the toxicological and pharmacological investigations given below show the interesting activities of the compounds of the formulas (I) and (II) obtainable according to the invention, in particular as antiinflammatory agents.

1) Toxicological examination

The compounds of the formulas (I) and (II) obtainable according to the invention have excellent compatibility and low toxicity. Thus, the LDcq / 24 h / kg animal determined on the mouse according to the method of Miller and Tainter when administered orally is above 800 mg for all derivatives.

For example, when administered intravenously to the mouse, derivative 1 had an IiDt = Q of 131

Further, experiments to determine the acute, chronic, subc-bironic and retarded toxicity in various animal species did not reveal any local or general response, any interference with the periodic biological controls and no abnormality in the microscopic and macroscopic examinations of the animals killed and autopsied after the experiment was completed , _:

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2) Pharmacological examination

The pharmacological examination has shown the anti-inflammatory activity of the compounds of formulas (I) and (II) obtainable according to the invention; it was carried out according to two Metboden;

a) Method of carrageenin-induced localized edema

A 1% carrageenin solution (0.1 ml) was injected into the right hind paw flexor muscles of the rat at time zero, animals of the treated group were also given orally 100 mg / kg body mass of the derivative 1b to be tested before and at the time of injection of the phlogogenic agent and then 1 b and 2 h after the injection. - ⁰ Ie with a ROCH micrometer at time zero, 1 b, 2 b, 3 h and 5 h after the administration of carrageenin measurements carried out have made it possible to determine in function of time, the percent anti-inflammatory activity by comparison with the control group.

The results are given in Table I below. . ·

T a belle I H after 2 h after 3 h after 5 h Derivative no. 46 45 48 49 48 49 52 50 49 49 51 52 Percent anti-inflammatory activity 1 2 3 4 after 1 43 40 42 45

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b) Method of generalized edema caused by egg white

1 ml of egg white and 0.5 ml of a 1% aqueous solution of Evans blue were injected intraperitoneally into the rat at the same time. In addition, the animals of the treated group were orally administered 100 mg / kg of body mass of the derivative to be examined 1 h before and simultaneously with the egg white. ^T he intensity of induced in this way appearance is rated with a number from 1 to 5 Depending on the progress of the inflammatory syndrome. In this way, the average edematous intensity and the percent reduction in the edematous response as a function of time were determined in comparison to the control animals.

The percent anti-inflammatory efficacy obtained 2 and 3 hours after injection of the whitening whiteness is given in the following Table II.

Table II

Derivative ITr. Percent anti-inflammatory activity after 2 h after 3 h '

1 44 50

2 49 58

3 53 61

4 48 60

The results of these experiments reveal the low toxicity and the interesting anti-inflammatory properties of the compounds of the formulas (I) and (II), which make them very valuable for use in human and veterinary medicine.

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The compounds of formulas (I) and (II) may be formulated for oral administration in the form of tablets, dragees, capsules, drops and syrup. Furthermore, they may be formulated for rectal administration in the form of suppositories and for parenteral administration in the form of injectable solutions.

Each unit dose advantageously contains 0.010 to 0.250 g of active ingredient. The doses to be administered may vary from 0.010 to 0.750 g of the active ingredient depending on the age of the patient and the condition to be treated.

The following are some examples of pharmaceutical compositions containing the compounds of the invention:

tablets

Derivative No. 1 0.100 g

Excipient cornstarch, lactose, gum

arabic, kieselguhr, magnesium

stearate

dragees

Derivative No. 4 0.075 g

Excipient talc, polyvinylpyrrolidone,

Magnesium stearate, potassium carbonate, rubber lake, gum arabic, sugar, titanium oxide, glucose, white wax, rosin, carnauba wax, lactose, sucrose, tartrazing oil, patent blue

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capsules

Derivative No. 3 0.150 g

Excipient V talc, cornstarch, stearin

acid

In _t jizierbare ampoules

Derivative no. 2 0.100 g

Excipient * isotonic solvent

q.s. 5 ω

suppositories

Derivative No. 4 0.100 g

Excipient semisynthetic triglycerides

Thus, the above-mentioned toxicological and pharmacological investigations prove the good compatibility of the compounds of formulas (I) and (II) obtainable according to the invention and their important anti-inflammatory activities.

Pharmaceutical preparations containing as active ingredient the compounds of formulas (I) and (II) can be advantageously used for the treatment of all inflammatory manifestations of any etiology, such as chronic inflammatory rheumatism, degenerative rheumatism, joint inflammation, neck -, nose and ear infections, injuries, dental and oral diseases as well as in postoperative surgery and gynecology.

Claims (4)

invention claim 1. A process for the preparation of new Thieno f2,3-cj - and - 3j2-cj pyridine derivatives of the general orm OH and OH (D (ID wherein E ,, and IL, which are identical or different and each represent hydrogen or alkyl, and their acid addition salts with pharmaceutically acceptable acids, characterized in that
a) a compound of the general formula OH or (VII). (VIII) with a sulfonyl chloride of the general formula ClSO ₂ H ₃ , wherein E ~ nied.Alkyl or optionally halogen or nied.alkyl-substituted phenyl, in one 26.4.1979 ..., 20 9 814 -19-. AP CO7D / 2O9 814 Two-phase loose agent system and in the presence of
Sodium carbonate condenses, b) the alcohols of the general formulas thus obtained or (V) _m (VI) oxidized in a solvent, - and c) the ketones of the general formula obtained in this way
0 -SO ₂ R ₃
N-SO ₂ R ₃ · """" with a base of the formula RO ^- M ⁺ , wherein R is optionally branched aliphatic alkyl and M ⁺
Cation of an alkali metal, treated in an alcohol of the formula ROH as a solvent and at the reflux temperature of the reaction mixture. 2. The method according to item 1, characterized in that as the solvent system in step a) a mixture of
Water and chloroform are used. I 26.4.1979 20 9 81 4- -2. ° '~ AP CO7D / 2O9 3 · Method according to item 1, characterized in that the oxidizing agent used in stage b) is a solution of chromic anhydride in sulfuric acid and the solvent acetone. 4. The method according to item 1, characterized in that is used as the base, a C, - ^ sodium or potassium alkoxide, such as potassium tert.butylat, and as alcohol ROH tert.Butylalkohol.